A negative feedback loop exists between the immune and central nervous systems, in which immune/pro-inflammatory mediators signal the hypothalamic corticotropin releasing hormone (CRH) neuron to promote pituitary-adrenal activation and, hence, glucocorticoid mediated restraint of the immune response. We have previously found that increased susceptibility to streptococcal cell wall (SCW)_induced arthritis in the Lewis (LEW/N) rat is related to a defect in the central component of this negative feedback loop, resulting in deficient CRH responses to challenge with a variety of inflammatory mediators, including streptococcal cell wall peptidoglycan polysaccharide (SCW), interleukin-1 alpha (IL-1 alpha) , or the serotonin agonist quipazine. The relative arthritis resistance of F344/N rats compared to LEW/N rats is related to their intact HPA axis responses to these same inflammatory mediators. Physiologic replacement doses of corticosteroids (dexamethasone) in LEW/N rats significantly suppressed the severity of the arthritis in this arthritis susceptible strain, while interruption of the axis in F344/N rats with the corticosteroid receptor antagonist RU486 was associated with development of severe systemic inflammation and arthritis in response to SCW in this otherwise inflammatory disease resistant strain. Interruption of the F344/N HPA axis at the level of serotonin stimulation, with the serotonin antagonist LY53857, was also associated with development of arthritis. Thus, whether present on a genetic basis, as in LEW/N rats, or on a pharmacologic basis, as in RU486 treated F344/N rats, we have shown that interruptions of the HPA axis are associated with susceptibility to inflammatory disease.